Genome-wide phenotypic profiling of transcription factors and identification of novel targets to control the virulence of Vibrio vulnificus.

For successful infection, the life-threatening pathogen Vibrio vulnificus elaborately regulates the expression of survival and virulence genes using various transcription factors (TFs). In this study, a library of the V. vulnificus mutants carrying specific signature tags in 285 TF genes was constructed and subjected to 16 phenotypic analyses.

The potential role of gut microbiota-derived metabolites as regulators of metabolic syndrome-associated mitochondrial and endolysosomal dysfunction in Alzheimer's disease.

Although the role of gut microbiota (GMB)-derived metabolites in mitochondrial and endolysosomal dysfunction in Alzheimer's disease (AD) under metabolic syndrome remains unclear, deciphering these host-metabolite interactions represents a major public health challenge. Dysfunction of mitochondria and endolysosomal networks (ELNs) plays a crucial role in metabolic syndrome and can exacerbate AD progression, highlighting the need to study their reciprocal regulation for a better understanding of how AD is linked to metabolic syndrome. Concurrently, metabolic disorders are associated with alterations in the composition of the GMB.

Sodium butyrate ameliorates high glucose-suppressed neuronal mitophagy by restoring PRKN expression via inhibiting the RELA-HDAC8 complex.

Damaged mitochondria accumulation in diabetes is one of the main features that contribute to increased incidence of cognitive impairment by inducing apoptosis. Butyrate is a major metabolite produced by microbiota that has neuroprotective effects by regulating mitochondrial function. However, detailed mechanisms underlying how butyrate can regulate neuronal mitophagy remain unclear.

Transcription Factor EB-Mediated Lysosomal Function Regulation for Determining Stem Cell Fate under Metabolic Stress.

Stem cells require high amounts of energy to replicate their genome and organelles and differentiate into numerous cell types. Therefore, metabolic stress has a major impact on stem cell fate determination, including self-renewal, quiescence, and differentiation. Lysosomes are catabolic organelles that influence stem cell function and fate by regulating the degradation of intracellular components and maintaining cellular homeostasis in response to metabolic stress.

Enhancing the therapeutic efficacy of mesenchymal stem cell transplantation in diabetes: Amelioration of mitochondrial dysfunction-induced senescence.

Mesenchymal stem cell (MSC) transplantation offers significant potential for the treatment of diabetes mellitus (DM) and its complications. However, hyperglycemic conditions can induce senescence and dysfunction in both transplanted and resident MSCs, thereby limiting their therapeutic potential. Mitochondrial dysfunction and oxidative stress are key contributors to this process in MSCs exposed to hyperglycemia.

Glucocorticoid enhances presenilin1-dependent Aβ production at ER's mitochondrial-associated membrane by downregulating Rer1 in neuronal cells.

Stress-induced release of glucocorticoid is an important amyloidogenic factor that upregulates amyloid precursor protein (APP) and β secretase 1 (BACE1) levels. Glucocorticoid also contributes to the pathogenesis of Alzheimer's disease (AD) by increasing ER-mitochondria connectivity, in which amyloid β (Aβ) processing occurs rigorously because of its lipid raft-rich characteristics. However, the mechanism by which glucocorticoid enhances γ-secretase activity in the mitochondrial-associated membrane of ER (MAM) and subsequent accumulation of mitochondrial Aβ is unclear.

TRIM16-mediated lysophagy suppresses high-glucose-accumulated neuronal Aβ.

Aβ: amyloid β; AD: Alzheimer disease; AMPK: 5' adenosine monophosphate-activated protein kinase; CTSB: cathepsin B; CTSD: cathepsin D; DM: diabetes mellitus; ESCRT: endosomal sorting complex required for transport; FBXO27: F-box protein 27; iPSC-NDs: induced pluripotent stem cell-derived neuronal differentiated cells; LAMP1: lysosomal-associated membrane protein 1; LMP: lysosomal membrane permeabilization; LRSAM1: leucine rich repeat and sterile alpha motif containing 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; p-MAPT/tau: phosphorylated microtubule associated protein tau; ROS: reactive oxygen species; STZ: streptozotocin; TFE3: transcription factor E3; TFEB: transcription factor EB; TRIM16: tripartite motif containing 16; UBE2QL1: ubiquitin conjugating enzyme E2 Q family like 1; VCP: valosin containing protein.

Melatonin-mediated FKBP4 downregulation protects against stress-induced neuronal mitochondria dysfunctions by blocking nuclear translocation of GR.

The physiological crosstalk between glucocorticoid and melatonin maintains neuronal homeostasis in regulating circadian rhythms. However, the stress-inducing level of glucocorticoid triggers mitochondrial dysfunction including defective mitophagy by increasing the activity of glucocorticoid receptors (GRs), leading to neuronal cell death. Melatonin then suppresses glucocorticoid-induced stress-responsive neurodegeneration; however, the regulatory mechanism of melatonin, i.

Ethanol-induced ceramide production causes neuronal apoptosis by increasing MCL-1S-mediated ER-mitochondria contacts.

Heavy alcohol consumption causes neuronal cell death and cognitive impairment. Neuronal cell death induced by ethanol may result from increased production of the sphingolipid metabolite ceramide. However, the molecular mechanisms of neuronal cell death caused by ethanol-induced ceramide production have not been elucidated.

Silencing SIRT5 induces the senescence of UCB-MSCs exposed to TNF-α by reduction of fatty acid β-oxidation and anti-oxidation.

Tumor necrosis factor-α (TNF-α) is an inflammatory cytokine involved in cell survival, apoptosis, and homeostasis. However, the regulatory effect of TNF-α on mesenchymal stem cell (MSC) redox regulation remains unknown. The process of delaying the senescence of MSCs and maintaining antioxidation mechanism is important in transplantation therapy to treat inflammatory diseases that result from restricted immunomodulatory effects of senescent MSCs.

Prenatal glucocorticoid exposure selectively impairs neuroligin 1-dependent neurogenesis by suppressing astrocytic FGF2-neuronal FGFR1 axis.

Exposure to maternal stress irreversibly impairs neurogenesis of offspring by inducing life-long effects on interaction between neurons and glia under raging differentiation process, culminating in cognitive and neuropsychiatric abnormalities in adulthood. We identified that prenatal exposure to stress-responsive hormone glucocorticoid impaired neurogenesis and induced abnormal behaviors in ICR mice. Then, we used human induced pluripotent stem cell (iPSC)-derived neural stem cell (NSC) to investigate how neurogenesis deficits occur.

High glucose-mediated VPS26a down-regulation dysregulates neuronal amyloid precursor protein processing and tau phosphorylation.

Background And Purpose: The relationship between hyperglycaemia-induced retromer dysfunction impairing intracellular trafficking and Alzheimer's disease (AD) remains unclear, although diabetes mellitus (DM) is considered a risk factor for AD. Here, we investigated the effects of high glucose on the retromer and defined the dysregulation of mechanisms of amyloid precursor protein (APP) processing and tau phosphorylation.

Experimental Approach: We used human induced-pluripotent stem cell-derived neuronal differentiated cells and SH-SY5Ys exposed to high glucose to identify the underlying mechanisms.

Cyanidin 3-O-arabinoside suppresses DHT-induced dermal papilla cell senescence by modulating p38-dependent ER-mitochondria contacts.

Background: Androgenetic alopecia (AGA) is a genetic disorder caused by dihydrotestosterone (DHT), accompanied by the senescence of androgen-sensitive dermal papilla cells (DPCs) located in the base of hair follicles. DHT causes DPC senescence in AGA through mitochondrial dysfunction. However, the mechanism of this pathogenesis remains unknown.

Statins Enhance the Molecular Response in Chronic Myeloid Leukemia when Combined with Tyrosine Kinase Inhibitors.

Previous studies have suggested that statins can be repurposed for cancer treatment. However, the therapeutic efficacy of statins in chronic myeloid leukemia (CML) has not yet been demonstrated. In this study, we retrospectively evaluated the outcomes of 408 CML patients who underwent imatinib therapy.

Intrathecal interleukin-1β decreases sigma-1 receptor expression in spinal astrocytes in a murine model of neuropathic pain.

The sigma-1 receptor (Sig-1R) plays an important role in spinal pain transmission by increasing phosphorylation of the N-methyl-D-aspartate (NMDA) receptor GluN1 subunit (pGluN1). As a result Sig-1R has been suggested as a novel therapeutic target for prevention of chronic pain. Here we investigated whether interleukin-1β (IL-1β) modulates the expression of the Sig-1R in spinal astrocytes during the early phase of nerve injury, and whether this modulation affects spinal pGluN1 expression and the development of neuropathic pain following chronic constriction injury (CCI) of the sciatic nerve.

Glucocorticoid impairs mitochondrial quality control in neurons.

Neurons are particularly vulnerable to mitochondrial dysfunction due to high energy demand and an inability to proliferate. Therefore, dysfunctional mitochondria cause various neuropathologies. Mitochondrial damage induces maintenance pathways to repair or eliminate damaged organelles.

Melatonin activates ABCA1 via the BiP/NRF1 pathway to suppress high-cholesterol-induced apoptosis of mesenchymal stem cells.

Background: Retarded wound healing in patients with obesity contributes to a risk of complications associated with vascular insufficiency and oxidative stress. The high cholesterol levels of patients with obesity are associated with apoptosis of engrafted umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs). Melatonin contributes to the prevention of cholesterol accumulation in patients with obesity via a mechanism that is poorly understood.

BNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects.

Stress-induced glucocorticoids disturb mitochondrial bioenergetics and dynamics; however, instead of being removed via mitophagy, the damaged mitochondria accumulate. Therefore, we investigate the role of glucocorticoids in mitophagy inhibition and subsequent synaptic defects in hippocampal neurons, SH-SY5Y cells, and ICR mice. First, we observe that glucocorticoids decrease both synaptic density and vesicle recycling due to suppressed mitophagy.